Design, synthesis, and evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer's disease.

Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer's disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, and showed submicromolar IC values (, eeAChE IC = 0.39 ± 0.11 µM; , eqBChE IC = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that and act in a competitive manner. and showed neuroprotective effect against HO-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay . Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of and was lower than tacrine. In summary, these data suggest and are promising multifunctional agents against AD.